BACKGROUND AND
OBJECTIVES: The association of drugs with different mechanisms of action
in the dorsal horn of the spinal cord decreases postoperative pain, with a reduction
in the incidence of side effects. The aim of this study was to evaluate postoperative
analgesia and sedation by epidural S(+) ketamine and S(+) ketamine-morphine
associated with ropivacaine in subcostal cholecystectomy.METHODS: Seventy patients of both genders, physical status ASA I and
II, participated in this study. The following drugs were administered epidurally:
0.75% ropivacaine associated with 0.9% sodium chloride in the Control Group
(CG); 0.75% ropivacaine associated with S(+) ketamine (0.5 mg.kg-1)
in the Ketamine Group (KG); 0.75% ropivacaine associated with S(+) ketamine
(0.5 mg.kg-1) and morphine (2 mg) in the Ketamine-Morphine Group2
(KMG2); 0.75% ropivacaine associated with S(+) ketamine (0.5 mg.kg-1)
and morphine (3 mg) in the Ketamine-Morphine Group3 (KMG3).
Analgesia and sedation were evaluated 2h, 6h, and 24h after the end of the surgery.RESULTS: Sedation was observed up to 2 hours after the end of the procedure
in KG, KMG2, and KMG3. Analgesia was effective in CG up
to 2 hours after the surgery, at 2h and 6h in KG, and at 2h, 6h, and 24h, in
KMG2 and KMG3.CONCLUSIONS: S(+) ketamine and the associations S(+) ketamine-morphine
promoted sedation up to 2h after the end of the surgical procedure. S(+) ketamine
promoted analgesia especially at the moment of the 2h observation, and the associations
of S(+) ketamine-morphine promoted analgesia especially at 2h and 6h after the
surgery.

The association of anesthetic agents and techniques has been
used to decrease the nociceptive impulses during the intra- and
postoperative periods, minimizing morbidity and mortality.

The actions of ketamine involve several receptors, such as:
muscarinic and nicotinic; opioids mu, delta, and kappa;
monoaminergic and voltage-dependent calcium channels; as a
non-competitive antagonist, its action involves the phencyclidine
area of the complex N-methyl-D-aspartate channel-receptor (NMDA).
It also blocks sodium channels in the central and peripheral
nervous systems 1.

The chyrality of the ketamine molecule produces two optical
isomers. The S(+) isomer (levorotatory) of ketamine, due to its
stereoaffinity for the phencyclidine receptor in the NMDA
channel, which causes a non-competitive inhibition of the
activation of the channel by glutamate, has more potent analgesic
and anesthetic properties despite a pharmacologic profile that is
similar to the R(-) isomer (dextrorotatory) and to racemic
ketamine 2,3,4.

Morphine, a hydrophilic opioid, produces spinal analgesia due
to its actions on the opioid receptors mu2,
kappa1, and delta1, as well as supra-spinal
analgesia due to its action on opioid receptors mu1,
kappa3, and delta25. There is
evidence that suggests that the loss of effectiveness of morphine
administered in the postoperative period is secondary to the
activation of the NMDA receptors 6.

Ropivacaine is a long-acting local anesthetic, chemically
homologous to mepivacaine and bupivacaine. Clinical studies
demonstrated that ropivacaine is less toxic to the cardiovascular
and central nervous systems when compared with bupivacaine
7.

The aim of this study was to evaluate the epidural
administration of S(+) ketamine and S(+) ketamine associated with
morphine in combination with ropivacaine in the postoperative
analgesia and sedation in upper abdominal surgeries.

METHODS

This study was approved by the Ethics Committee on Human
Research of the Universidade do Vale do Sapucaí. Patients
were required to sign an informed consent after careful
explanation of the procedures. Seventy patients, both genders,
with ages ranging from 18 to 50 years, physical status ASA I and
II, undergoing subcostal cholecystectomy under general anesthesia
associated with thoracolumbar epidural anesthesia participated in
this analytical, interventional, clinical, prospective,
randomized, double-blind study.

Thoracolumbar epidural anesthesia was performed with the
patient in the sitting position, in the
T12-L1 space with a 15G Tuohy needle.
Patients were randomly assigned to receive 20 mL of 0.75%
ropivacaine associated with: 1 mL of 0.9% sodium chloride in the
control Group (CG, n = 10); 0.5 mg.kg-1 of S(+)
ketamine in the Ketamine Group (KG, n = 20); 0.5
mg.kg-1 of S(+) ketamine and 2 mg of morphine in the
Ketamine-Morfine2 Group (KMG2, n = 20); and
0.5 mg.kg-1 of S(+) ketamine and 3 mg of morphine in
the Ketamine-Morphine3 Group (KMG3, n =
20). A predetermined volume of the drug combinations was
administered in the epidural space of every patient at a rate of
1 mL.sec-1. Afterwards, patients returned to the
supine position and the level of the sensitive blockade was
tested, as well as monitoring of the blood pressure and heart
rate up to 15 minutes after the administration of the epidural
anesthesia.

Ethomidate (0.2
mg.kg-1), alfentanyl (30 µg.kg-1), and rocuronium
(0.6 mg.kg-1) were used for the anesthetic induction, while isoflurane
(0.5 vol% to 3.0 vol% of inspired concentration) was used for the maintenance.
When clinical or hemodynamic signs suggested inadequate levels of anesthesia
(diaphoresis, tearing, hypertension, and tachycardia), intermittent doses of
alfentanyl (500 µg) were administered intravenously.

Controlled ventilation was achieved with a low-flow anesthesia
system, which allowed for the humidification and heating of the
inspired gases. A tidal volume of 8 to 10 mL.kg-1 was
used and the respiratory frequency was adjusted to maintain the
expired pressure of carbon dioxide (PETCO2)
between 30 mmHg and 35 mmHg.

Blood pressure, heart rate, hemoglobin saturation
(SpO2), expired carbon dioxide
(PETCO2), and the inspired concentration of
isoflurane were recorded after placement of the monitoring
system, epidural anesthesia, tracheal intubation, and every 15
minutes thereafter until the end of the surgery. After the
procedure, patients were transferred to the recovery room.

Intraoperative analgesia was assessed by observing the
clinical signs, while the inspired concentration of the
inhalational agent was evaluated by a gas analyzer. An increase
in heart rate and/or systolic blood pressure above pre-block
levels were treated by increasing the inspired concentration of
isoflurane (up to 3.0 vol%) and, when the parameters did not
reach appropriate levels, a bolus of intravenous
alfentanyl (500 µg) was administered and repeated as many times
as necessary. A reduction in systolic blood pressure greater than
30% of pre-block levels or below 90 mmHg was treated with the
intravenous administration of a mixed action sympathomimetic
amine (ephedrine). A marked reduction in heart rate, below 50
bpm.min-1, causing a decrease in cardiac output, was
treated with intravenous atropine.

Regarding postoperative analgesia, pain severity was analyzed
by the Verbal Analogical Pain Scale in which zero corresponds to
the absence of pain and ten corresponds to the worse pain
possible. In this study, zero was used as a reference.

As for the postoperative
sedation, continuous changes in the alertness status may be as profound as unconsciousness;
the levels of depression of consciousness may vary from light to severe. With
light sedation, the level of depression is minimal and the patient makes contact
with the surrounding environment, follows commands, distinguishes events, and
reports facts. The numerical scale proposed by Filos was used to evaluate the
level of consciousness: 1  awaken and nervous; 2  awaken and calm;
3  sleepy, but easily arousable; 4  sleepy and difficulty to arise
8. In this study, a score of 3 was used as a reference of sedation.

Analgesia and sedation were evaluated at 2, 6, and 24 hours
after the surgical procedure. Postoperative pain was treated
systemically by the intravenous route. Initially, dypirone was
administered as the analgesic agent. If the patient still
complained of pain, tramadol, an opioid that causes less
depression and is less sedative than morphine, was added.

The Analysis of Variance with Scheffé's proof was used
for the statistical analysis of the anthropometrics data of the
patients; Student t test was used to analyze the duration
of the surgical procedure; Fisher exact test was used for the
statistical analysis of the drops in systolic blood pressure and
heart rate; Analysis of Variance with Tukey test were used for
the statistical analysis of the inspired concentrations of
isoflurane in CG, KMG2, and KMG3.
Chi-square and Fisher exact tests were used for the statistical
analysis of the analgesia. The Chi-square test was used for the
statistical analysis of the sedation. A p < 0.05 was
considered significant.

RESULTS

There were no statistically
significant differences in weight and age among the groups (Table
I).

Regarding the duration
of the surgery, there were no statistically significant differences among the
groups (Table II).

The levels of the sensitive blockade achieved by the
thoracolumbar anesthesia performed before the induction of
general anesthesia were similar in CG, KMG2, and
KMG3, with a median at the T6 level (margin
of the rib cage). The median for KG was the T3 level
(nipple).

Twelve patients
in KG, 10 in KMG2, and 7 in KMG3 presented a decrease
in systolic blood pressure greater than 30% of pre-blockade levels or below
90 mmHg. Fisher exact test demonstrated a statistically significant difference
between the Control Group and the Ketamine and Ketamine-Morphine2
Groups (Table III).

A marked reduction
in heart rate, below 50 beats.min-1, led to a reduction in cardiac
output in 3 patients in KG (40 beats.min-1) and in 1 patient in KMG3
(30 beats.min-1). Fisher exact test did not demonstrate statistically
significant differences among the groups (Table
III).

There was a dose-dependent
reduction in the inspired concentration of isoflurane related to morphine, with
a mean of 0.65% vol in KG, 0.70% vol in KMG2, and 0.52% vol in KMG3.
Using Analysis of Variance associated with Tukey test to compare the inspired
concentrations of the inhalational agents used in the Ketamine, Ketamine-Morphine2,
and Ketamine-Morphine3 Groups demonstrated a statistically significant
difference between the Ketamine-Morphine3 Group and the Ketamine
and Ketamine-Morphine2 Groups (Tabela IV).

Every patient in
the Control Group, who received only 0.75% ropivacaine, needed a mean inspired
concentration of isoflurane of 2.35% vol (Table IV) and
four patients also received intermittent doses of alfentanyl that ranged from
500 µg to 1500 µg.

As for postoperative
analgesia: at 2 hours, there was a statistically significant difference when
comparing the Control Group to the other groups; at 6 hours and 24 hours, there
was a statistically significant difference when comparing KG with the Ketamine-Morphine
Groups (Table V).

In the Ketamine
Group, patients who required supplemental analgesia received only dypirone 2
hours after the procedure; between 2 and 6 hours, 4 patients required the association
of tramadol and dypirone; between 6 and 24 hours, 2 more patients required the
association tramadol-dypirone (Table VI).

In KMG2,
dypirone was administered to the patients that required supplemental analgesia
up to 2 hours after the procedure; between 2 and 6 hours, patients received
dypirone and 2 patients also required the association with tramadol; however,
between 6 and 24 hours only dypirone was administered (Tabela
VI).

In KMG3,
dypirone was administered to every patient who needed supplemental analgesia
at the 2-hour observation; between 2 and 6 hours, dypirone was administered
but 2 patients also required the association with tramadol; between 6 and 24
hours, dypirone was administered to the patients who required supplemental analgesia
and the association dypirone-tramadol was administered to the same patients
of the prior period (Table VI).

There were no statistically
significant differences regarding sedation at the 2-hour observation between
the Ketamine Group and the Ketamine-Morphine Groups (Table
VII).

DISCUSSION

Regarding intraoperative analgesia, there was a reduction in
heart rate and blood pressure in every patient who received S(+)
ketamine, S(+) ketamine-morphine2, or S(+)
ketamine-morphine3 due to S(+) ketamine-mediated
blockade of the NMDA receptors and/or morphine-induced peripheral
vasodilation, decreased peripheral resistance, and inhibition of
the baroreceptors, as well as the sympathetic blockade induced by
the epidural administration of ropivacaine; patients did not need
intraoperative supplemental analgesia. The doses of alfentanyl
were the used during anesthetic induction, ranging between 1500
µg and 2700 µg.

There is a increasing number of studies demonstrating that low
doses of ketamine may play an important role in the treatment of
postoperative pain when used in association with local
anesthetics, opioids, or other analgesic drugs 1. The
concept of balanced analgesia deserves attention 9,10,
stretching the limits of analgesia using opioids 11.
The combination of drugs with different mechanisms of action in
the dorsal horn of the spinal cord decreases postoperative pain
and, at the same time, reduces the incidence of side effects.
This approach is known as balanced or multimodal analgesia
12. In this study, we used a local anesthetic,
ropivacaine, an opioid, morphine, and a non-competitive
antagonist of the N-methyl-D-aspartate receptor, ketamine, to
achieve the desired effects of the multimodal analgesia.

The meta-analysis of the preemptive analgesia demonstrated a
possible efficacy of this method in the treatment of acute
postoperative pain in selected analgesia regimens (epidural,
local anesthesia, antagonists of the N-methyl-D-aspartate acid,
non-steroidal anti-inflammatories and opioids) based on pain
scores, consumption of analgesics, and length of time until the
patient requests the first analgesic 13.

A study with patients who underwent gastrectomy showed that
the group that received epidural morphine associated with
intravenous ketamine had lower Visual Analogic Scale values and
required less morphine than the groups who received epidural
morphine, intravenous ketamine, and control groups (epidural and
intravenous normal saline). The medications were administered
before the conclusion of the surgical procedure in every group
14.

A study with patients who underwent upper abdominal surgeries
under general anesthesia and continuous epidural anesthesia
demonstrated that the patients who received pre-incisional
epidural ketamine, morphine, and bupivacaine experienced a
greater relief of postoperative pain than the patients who
received the same drugs via the same route after the skin
incision 15.

A study with patients who received patient-controlled epidural
analgesia for lower abdominal surgeries showed that analgesia was
more effective in patients who were treated with the association
morphine-ketamine, being necessary a lower dose of morphine, and
with a reduced incidence of side effects when compared with the
patients who were treated with morphine alone 16.

The study of Pugh et al. with children who presented low risk
in the evaluation of liver function by the modified Child
classification, suggested that the postoperative analgesia
provided by a single epidural injection of morphine associated
with low-dose ketamine is effective and safe, representing an
alternative technique of analgesia in patients with cirrhosis who
undergo any type of surgical intervention in the upper abdomen
17.

A study with patients treated with patient controlled epidural
analgesia (PCEA) with morphine, bupivacaine, and epinephrine,
with or without ketamine, for surgeries involving the thorax and
upper abdomen, concluded that adding ketamine to a multimodal
PCEA regimen reduces postoperative pain and the use of analgesics
18.

Another study evaluated the safety and efficacy of epidural
ketamine associated with morphine in the postoperative period of
upper abdominal surgeries, demonstrated that the addition of
ketamine improved analgesia but did not increase the incidence of
side effects 19.

In this study, we observed that the use of multimodal
analgesia with S(+) ketamine, morphine, and ropivacaine promoted
a more prolonged analgesia and decreased the use of analgesics,
which is similar to the results of other studies, but increasing
the dose of morphine did not improve analgesia and did not
decrease the use of analgesics.

A study with children with liver disease concluded that there
were no statistically significant differences between the
morphine and morphine-ketamine groups regarding the respiratory
variables (partial arterial pressure of carbon dioxide and
respiratory rate) and sedation 17.

A study with patients who received morphine, bupivacaine, and
epinephrine, with or without ketamine, for surgeries in the
thorax and upper abdomen concluded that the patients presented an
easy awakening without statistically significant differences
regarding sedation between the groups that received morphine,
bupivacaine, and epinephrine and the group receiving the same
drugs associated with ketamine 18.

A work with patients who received epidural morphine associated
with ketamine for surgeries of the upper abdomen demonstrated
that patients who received ketamine with morphine had higher
sedation scores in the first two hours after the surgery then
patients treated with morphine alone 19.

In the current study, patients who received S(+) ketamine or
S(+) ketamine associated with morphine were sedated 2 hours after
the surgical procedure without statistically significant
differences among the groups, which confirms the results of two
of the authors mentioned before but goes against the results of
another author.

Epidural S(+) ketamine and S(+) ketamine-morphine associated
with ropivacaine produced longer lasting sedation and analgesia
and reduced the amount of analgesics used in the postoperative
period of surgeries of the upper abdomen.

REFERENCES

01. Schmid RL, Sandler AN, Katz J - Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain, 1999;82:111-125. [ Links ]